Abstract
miR-145 is an important repressor of pluripotency in embryonic stem cells and a tumor suppressor in different cancers. Here, we found that miR-145 is strongly down-regulated in glioblastoma (GB) specimens and corresponding glioblastomaneurospheres (GB-NS, containing GB stem-like cells) compared to normal brain (NB) and to low-grade gliomas (LGG). We observed a direct correlation between miR-145 expression and the progression-free survival (PFS) in LGG patients and overall survival (OS) in GB patients. Using microarray analysis, we identified relevant differences in gene expression profiles between GB-NS over-expressing miR-145 (miRover-NS) and GB-NS Empty (Empty-NS). We focused our attention on HEF1/Cas-L/NEDD9, a scaffold protein involved in invasion in several types of cancer. We confirmed a significant down-regulation of NEDD9 in miRover-NS and we found a higher expression in GB and GB-NS compared to NB. Approximately 50% of LGG patients expressed higher levels of NEDD9 than NB, and the PFS of such patients was shorter than in patients expressing lower levels of NEDD9. We observed that intracranial injection of GB-NS over-expressing miR-145 delays significantly tumor development :deriving tumors showed a significant down-regulation of NEDD9. In addition, we demonstrated a significant inhibition of invasion in silencing experiments with GB-NS shNEDD9 (shNEDD9), and an up-regulation of miR-145 in shNEDD9, suggesting a doublenegative feedback loop between miR-145 and NEDD9. Our results demonstrate the critical role of miR-145 and NEDD9 in regulating glioblastoma invasion and suggest a potential role of NEDD9 as a biomarker for glioma progression.
Highlights
Glioblastomas (GB) and other cancers may contain a populations of cells expressing stem cell programs and sharing expression patterns with embryonic stem cells [1]
We attempted an in-depth characterization of the microRNA expression profiles of glioblastoma (GB) specimens, primary cell lines derived from GB growing as neurospheres (GB-NS) in the presence of b-fibroblast growth factor (b-FGF) and epidermal growth factor (EGF)
We evaluated the expression levels of different microRNAs previously known to be down-regulated in both tumors and stem cells: miR128a [15], let7a [16], miR181a [17], miR101 [18], and miR-145. miR128a is a typical brain-enriched miRNA that is usually up-regulated during differentiation and development; we found miR128a down-regulated in GB cell lines (GB-NS) compared to normal brain tissue. miRNA let7a is typically down-regulated in many cancers [19,20,21], whereas miR181 is mainly up-regulated during differentiation [22]
Summary
Glioblastomas (GB) and other cancers may contain a populations of cells expressing stem cell programs and sharing expression patterns with embryonic stem cells [1]. Oct-4, Sox-2 and Nanog are core genes in embryonic stem cell maintenance and they are all up-regulated in GB and malignant gliomas [2]. MiRNAs are able to regulate the expression of more than 30% of human genes via specific base pairing to the 3’-UTRs of messenger RNAs, which either blocks translation or promotes the degradation of the mRNA target. MiRNAs are posttranscriptional modulators of gene expression and are involved in the regulation of several cellular processes, such as the cell cycle, apoptosis, proliferation and development. The abnormal expression of miRNAs is associated with several examples of human tumorigenesis: as such miRNAs may represent a novel, important class of oncogenes or tumor suppressor genes [5], [6]. MiR-145 is induced by the tumor suppressor gene www.impactjournals.com/oncotarget
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